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Foundations
in
Microbiology
Fifth Edition
Talaro
Chapter
12
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Drugs, Microbes, Host The

Elements of Chemotherapy
Chapter 12

Origins of antimicrobial drugs

Antibiotics are common metabolic products of
aerobic spore-forming bacteria & fungi.
bacteria in genera Streptomyces & Bacillus
molds in genera Penicillium & Cephalosporium
By inhibiting the other microbes in the same
habitat, antibiotic producers have less
competition for nutrients & space.
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Selectively toxic
Drugs should kill or inhibit microbial cells
without simultaneously damaging host
tissues.
As the characteristics of the infectious agent
become more similar to the vertebrate host
cell, complete selective toxicity becomes
more difficult to achieve & more side effects
are seen.
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Targets of antimicrobial drugs

1. Inhibition of cell wall synthesis
2. Inhibition of nucleic acid synthesis,
structure or function
3. Inhibition of protein synthesis
4. Disruption of cell membrane structure or
function

Targets of antimicrobial drugs

1. Drugs that affect the bacterial cell

wall
Most bacterial cell walls contain a rigid girdle of
peptidoglycan.
Penicillin and cephalosporin block synthesis of
peptidoglycan, causing the cell wall to lyse.
Penicillins do not penetrate the outer membrane and
are less effective against gram-negative bacteria.
Broad spectrum penicillins and cephalosporins can
cross the cell walls of gram-negative bacteria.
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1. Drugs that affect the bacterial cell

wall

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1. Drugs that affect the bacterial cell

wall

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2. Drugs that inhibit nucleic acid

synthesis

may block synthesis of nucleotides, inhibit

replication, or stop transcription
Sulfonamides and trimethoprim block enzymes
required for tetrahydrofolate synthesis needed
for DNA & RNA synthesis.
competitive inhibition drug competes with
normal substrate for enzymes active site
synergistic effect an additive effect,
achieved by multiple drugs working together,
requiring a lower dose of each
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2. Drugs that inhibit nucleic acid

synthesis

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3. Drugs that block protein synthesis

Ribosomes of eucaryotes differ in size and
structure from procaryotes, so antimicrobics
usually have a selective action against
procaryotes. But they can also damage the
eucaryotic mitochondria.
Aminoglycosides (streptomycin, gentamicin)
insert on sites on the 30S subunit and cause
misreading of mRNA.
Tetracyclines block attachment of tRNA on the
A acceptor site and stop further synthesis.
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3. Drugs that block protein synthesis

15

4. Drugs that disrupt cell membrane

function
A cell with a damaged membrane dies from
disruption in metabolism or lysis.
These drugs have specificity for a particular
microbial group, based on differences in types of
lipids in their cell membranes.
Polymyxins interact with phospholipids and
cause leakage, particularly in gram-negative
bacteria
Amphotericin B and nystatin form complexes
with sterols on fungal membranes which causes
leakage.
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4. Drugs that disrupt cell membrane

function

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Survey of major antimicrobial drug

groups
Antibacterial drugs
Antibiotics
Synthetic drugs

Antifungal drugs
Antiparasitic drugs
Antiviral drugs
About 260 different antimicrobial drugs are
classified in 20 drug families.
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Antibacterial antibiotics

Penicillins
Cephalosporins
Other beta-lactam antibiotics
Aminoglycosides
Tetracycline antibiotics
Chloramphenicol
Other Streptomyces antibiotics
The Bacillus antibiotics
New classes
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Penicillins
Large diverse group of compounds
Could be synthesized in the laboratory
more economical to obtain natural penicillin through
microbial fermentation and modify it to semisynthetic forms
Penicillium chrysogenum major source
All consist of 3 parts
thiazolidine ring
beta-lactam ring
variable side chain dictates microbial activity

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Penicillins

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Penicillins
Penicillins G and V most important natural forms
Penicillin is the drug of choice for gram-positive
cocci (streptococci) and some gram-negative bacteria
(meningococci and syphilis spirochete)
Semisynthetic penicillins ampicillin, carbenicillin
& amoxicillin have broader spectra gram negative
enterics rods
Penicillinase-resistant methicillin, nafcillin,
cloxacillin
Primary problems allergies and resistant strains of
bacteria
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Cephalosporins
Account for majority of all antibiotics
administered
Isolated from Cephalosporium acremonium mold
Beta-lactam ring that can be altered
Relatively broad-spectrum, resistant to most
penicillinases, & cause fewer allergic reactions
Some are given orally, many must be administered
parenterally
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Cephalosporins

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Cephalosporins
3 generations exist
First generation cephalothin, cefazolin most
effective against gram-positive cocci
Second generation cefaclor, cefonacid more
effective against gram-negative bacteria
Third generation cephalexin, cefotaxime broadspectrum activity against enteric bacteria with betalactamases
Ceftriaxone new semisynthetic broad-spectrum drug
for treating wide variety of infections
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Other beta-lactam antibiotics

Imipenem broad-spectrum drug for
infections with aerobic and anaerobic
pathogens
Azeotreonam isolated from bacteria
Chromobacterium violaceum newer
narrow-spectrum drug for infections by
gram-negative aerobic bacilli. May be used
by people allergic to penicillin.
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Aminoglycosides
composed of 2 or more amino sugars and an
aminocyclitol (6C) ring
products of various species of soil actinomycetes in
genera Streptomyces & Micromonospora
Broad-spectrum, inhibit protein synthesis, especially
useful against aerobic gram-negative rods & certain
gram-positive bacteria
Streptomycin bubonic plague, tularemia, TB
Gentamicin less toxic, used against gram-negative rods
Newer Tobramycin & amikacin gram-negative bacteria
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Aminoglycosides

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Tetracycline antibiotics
Broad-spectrum, block protein synthesis
Doxycycline & minocycline oral drugs
taken for STDs, Rocky Mountain spotted
fever, Lyme disease, typhus, acne &
protozoa

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Chloramphenicol
Isolated from Streptomyces venezuelae
Potent broad-spectrum drug with unique
nitrobenzene structure
Blocks peptide bond formation
No longer derived from natural source
Very toxic, restricted uses, can cause irreversible
damage to bone marrow
Typhoid fever, brain abscesses, rickettsial &
chlamydial infections
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31

Other Streptomyces antibiotics

Erythromycin macrolide, large lactone ring with
sugars
Broad-spectrum, fairly low toxicity
Attaches to ribosome
Taken orally for Mycoplasma pneumonia,
legionellosis, Chlamydia, pertussis, diptheria and
as a prophylactic prior to intestinal surgery
For penicillin-resistant gonococci, syphilis, acne
Newer semi-synthetic macrolides clarithomycin,
azithromycin
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Other Streptomyces antibiotics

Clindamycin broad-spectrum, serious
abdominal anaerobic infections
Vancomycin narrow-spectrum, effective
against penicillin & methicillin resistant
staphylococcal infections; very toxic, hard to
administer
Rifampin limited spectrum, cannot pause
through many cell membranes, used to treat
gram-positive bacteria, TB, leprosy
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The Bacillus antibiotics

Bacitracin- narrow-spectrum peptide
produce by Bacillus subtilis, major
ingredient of neosporin ointment
Polymyxin - narrow-spectrum peptide with
fatty acid component, detergent activity;
limited by toxicity to kidney; drug resistant
Pseudomonas aeruginosa & UTI
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New classes of antibiotics

Fosfomycin trimethamine a phosporic
acid effective as alternate treatment for
UTIs, inhibits cell wall synthesis
Synercid effective against Staphylococcus
& Enterococcus that cause endocarditis &
surgical infections; inhibits protein
synthesis
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Synthetic antibacterial drugs

Sulfonamides, sulfa drugs first
antimicrobic drugs
Sulfisoxazole shigellosis, UTI, protozoan
infections
Silver sulfadiazine burns, eye infections
Trimethoprim given in combination with
sulfamethoxazole UTI, PCP
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Sulfonamides

37

Miscellaneous antibacterial drugs

Isoniazid used with rifampicin to treat TB
Oxazolidinones- new class of antibacterial drugs
inhibit initiation of protein synthesis
Linezolid MRSA, VRE

Fluoroquinolones broad-spectrum, potent

norfloxacin, ciprofloxacin UTI, STD, GI,
osteomyletitis, respiratory & soft tissue infections
sparofloxacin, levofloxacin pneumonia, bronchitis,
sinusitis
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Antifungal drugs
Macrolide polyene
Amphotericin B mimic lipids, most versatile &
effective, topical & systemic treatments
Nystatin topical treatment

Griseofulvin stubborn cases of dermatophyte

infections, nephrotoxic
Synthetic azoles broad-spectrum; ketoconazole,
clotrimazole, miconazole
Flucytosine analog of cytosine; cutaneous
mycoses or in combination with amphotericin B for
systemic mycoses
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Antifungal drugs

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Antiparasitic drugs
Antimalarial drugs quinine, chloroquinine,
primaquine, mefloquine
Antiprotozoan drugs - Metronidazole (Flagyl),
quinicrine, sulfonamides, tetracyclines
Antihelminthic drugs immobilize, disintegrate, or
inhibit metabolism
mebendazole, thiabendazole- broad-spectrum inhibit
function of microtubules, interfers with glucose utilization &
disables them
pyrantel, piperazine- paralyze muscles
niclosamide destroys scolex

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Antiviral drugs

Block penetration into host cell

Block transcription or translation

Nucleotide analogs

Prevent maturation of viral particles

Acyclovir herpesviruses
Ribavirin- a guanine analog RSV, hemorrhagic fevers
AZT thymine analog - HIV

Protease inhibitors HIV

Interferon - HCV
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Mechanisms drug resistance

Drug inactivation penicillinases
Decreased permeability to drug or increased
elimination of drug from cell
Change in metabolic patterns
Change in drug receptors

43

Mechanisms drug resistance

44

Selection for drug resistance

45

Side effects of drugs

1. Toxicity to organs
2. Allergic responses
3. Suppression and alteration of microflora

46

47

48

Considerations in selecting an
antimicrobial drug
1. nature of microbe causing infection
2. degree of microbes sensitivity to various
drugs
3. overall medical condition of patient

49

 Minimum inhibitory concentration (MIC)smallest concentration of drug that visibly

inhibits growth
Therapeutic index the ratio of the dose of
the drug that is toxic to humans as
compared to its minimum effective dose

50